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Chymase increases glomerular albumin permeability via protease-activated receptor-2

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Abstract

Increased infiltration of the kidney by mast cells is associated with proteinuria, and interstitial fibrosis in various renal diseases. Mast cells produce serine proteases including tryptase and chymase (MCC) that act via protease-activated receptors (PARs) to induce synthesis of fibrogenic cytokines by renal cells. In the present study, we investigated direct effect of MCC and role of PARs on glomerular albumin permeability (Palb). Isolated rat glomeruli were incubated with MCC (0.1, 1, 10, and 100 ng/ml) for 5–30 min in presence or absence of PAR-1 and PAR-2 blocking antibodies. Palb was determined from the change in glomerular volume in response to an albumin oncotic gradient. The effect of direct activation of PARs on Palb was verified by incubating glomeruli with synthetic hexapeptide known to activate PAR-1 and PAR-2. MCC increased Palb of isolated rat glomeruli in a dose- and time-dependent manner. Blocking PAR-2 prevented MCC-mediated increase in Palb. RT-PCR analysis of glomerular RNA demonstrated the presence of constitutively expressed PAR-1, -2, and -3 and low levels of PAR-4. In addition, direct activation of PAR-2 by hexapeptide SLIGKV increased Palb comparable to MCC, whereas PAR-1 activation by TFLLRN had no effect on Palb. Our results document that MCC induces increase in Palb and that this effect is mediated through PAR-2. MCC may also play a role in renal scarring. We propose that inhibiting MCC activity or blocking the activation of PAR-2 may provide new targets for therapy in renal diseases.

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Abbreviations

MCC:

mast cell chymase

PARs:

protease-activated receptors

Palb :

glomerular albumin permeability

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Acknowledgments

This work was supported by funds from the Midwest Biomedical Research Foundation, Kansas City, MO (Ram Sharma) and NIH/NIDDK RO1 DK 064969 (Ellen T. McCarthy). Portions of these data have been presented at the 39th Annual Meetings of the American Society of Nephrology (November 5–8, 2006, San Diego, CA).

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Authors and Affiliations

  1. Renal Research Laboratory, Kansas City VA Medical Center, 4801 Linwood Boulevard, Kansas City, MO, 64128, USA

    Ram Sharma & Thomas Wiegmann

  2. Neurobiology Research Laboratory, Kansas City VA Medical Center, Kansas City, MO, USA

    Vidudala Prasad

  3. Division of Nephrology, University of Kansas Medical Center, Kansas City, KS, USA

    Ellen T. McCarthy

  4. Division of Nephrology, Medical College of Wisconsin, Milwaukee, WI, USA

    Virginia J. Savin & Mukut Sharma

  5. Division of Allergy, Clinical Immunology and Rheumatology, Department of Medicine, University of Kansas Medical Center, Kansas City, KS, USA

    Kottarappat N. Dileepan & Daniel J. Stechschulte

  6. Division of Nephrology, Department of Medicine, University of Medicine and Dentistry, New Jersey-Robert Wood Johnson Medicine School, New Brunswick, NJ, USA

    Elias Lianos

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  1. Ram Sharma
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  2. Vidudala Prasad
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Correspondence to Ram Sharma.

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Sharma, R., Prasad, V., McCarthy, E.T. et al. Chymase increases glomerular albumin permeability via protease-activated receptor-2. Mol Cell Biochem 297, 161–169 (2007). https://doi.org/10.1007/s11010-006-9342-0

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  • DOI: https://doi.org/10.1007/s11010-006-9342-0

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